Читать книгу Cases in Medical Microbiology and Infectious Diseases - Melissa B. Miller - Страница 65

1. The patient was infected with Bordetella pertussis, the causative agent of whooping cough. With classic whooping cough, children have paroxysmal coughing, which is a series of coughs during a single expiration. Paroxysms are often accompanied by a “whoop” sound in children due to rapid inspiration through a narrow trachea. (An audio file of a child with pertussis can be found at www.immunizationed.org.) Because of repetitive coughing and resulting disruption of breathing, children will have abnormal oxygen exchange and will often turn red and sometimes blue. The repetitive coughing may also result in vomiting or choking on respiratory secretions. Although the classic “whooping” sound was not described for this child, she did have bouts of coughing leading to increased respiration, decreased oxygenation, and posttussive vomiting. In infants <6 months old, apnea is more common than whooping inspirations. Further, the patient had a lymphocytosis, which is commonly seen in pertussis. Although the etiologic agent is a bacterium, the disease is toxin mediated, explaining the rise in lymphocyte count. Historically, the pertussis toxin (a key virulence factor of B. pertussis) has also been described as the “lymphocytosis-promoting factor.” Clinically, lymphocytosis, often as high as 70 to 80%, is routinely seen in patients with pertussis and is a distinguishing characteristic of this infection.

2. B. pertussis specifically binds to ciliated epithelial cells. This binding is mediated primarily by filamentous hemagglutinin, an important virulence factor of this organism. Since the nasopharynx is lined with ciliated epithelial cells, it is the most sensitive site for the detection of B. pertussis.

Culture has long been the gold standard for the laboratory diagnosis of pertussis owing to its superior specificity (~100%). However, there are many disadvantages to B. pertussis culture. First, the organism is very labile outside of the host. Second, it must be cultivated on specialized media such as Bordet-Gengou or Regan-Lowe agar. These attributes make the bacterium difficult to isolate. Third, it generally takes 7 to 10 days to isolate and identify B. pertussis from culture. In Fig. 9.1, we see an isolate of B. pertussis that grew after 7 days of incubation on a charcoal-containing medium, Regan-Lowe agar. In outbreak settings where B. pertussis can be rapidly spread from person to person, culture is too slow. Lastly, the clinical course of pertussis is complex (see answer 3), and the organism is generally only recovered during the first 2 weeks of illness. Sensitivity of culture during the first 2 weeks of pertussis is 30 to 60%, and it drops dramatically (1 to 3%) by the third week of illness. Sensitivity of culture is also negatively affected by antibiotic administration and prior vaccination. Nonetheless, the Centers for Disease Control and Prevention (CDC) recommends culturing of nasopharyngeal specimens during an outbreak so that specificity is preserved and isolates are obtained for susceptibility testing and epidemiologic studies.

Figure 9.1 Organism infecting this patient.

For many years, direct fluorescent-antibody assay (DFA) for B. pertussis was done. This assay takes ~2 hours, versus 7 to 10 days for culture, but it has a sensitivity of only 50 to 65%, and false-positive results may occur, especially when laboratorians are unaccustomed to reading these DFA smears. DFA is no longer in the CDC’s diagnostic algorithm for pertussis because of these limitations.

NAAT, and in particular PCR, has become the method of choice for diagnosing pertussis. Because PCR does not require that the organisms be alive, it is useful when specimens must be transported long distances. PCR is more rapid than culture, with results often available the same day the specimen was collected. PCR is more sensitive than culture and has a high negative predictive value. There are two FDA-cleared molecular products for the detection of B. pertussis. One is a 20-plex test that detects a number of respiratory viruses and bacteria simultaneously, while the other is a stand-alone test. Many laboratories use laboratory-developed NAATs for the detection of B. pertussis. The performance of these tests varies widely. Sensitivity and specificity are dependent on the target used for amplification, with the most sensitive tests targeting multicopy sequences and the most specific tests detecting multiple targets. The primary concern for PCR-based diagnosis of pertussis is the risk of false-positive results. False-positive PCR results have been the subject of “pseudo” outbreaks of pertussis that have been linked to cross-reacting Bordetella spp. (e.g., B. holmesii), laboratory contamination, and environmental contamination at collection. Interestingly, it has been reported that false-positive results can occur when specimens are collected in the same clinic room where pertussis vaccines (some of which contain genomic DNA) are administered. Since there is no perfect test for the diagnosis of pertussis, the CDC recommends that both culture and PCR be used diagnostically.

3. The clinical course of pertussis is defined by three stages: catarrhal, paroxysmal, and convalescent. The catarrhal phase lasts 1 to 2 weeks, but symptoms are often nonspecific and are similar to those of many respiratory viral illnesses (malaise, low-grade fever, rhinorrhea, and mild cough). Laboratory diagnosis is most sensitive at this phase, but laboratory testing (particularly in adolescents and adults) is often not performed. Even though pertussis is a toxin-mediated disease, appropriate antimicrobial therapy during the catarrhal stage decreases the organism load, thereby reducing the infectiousness of the patient, the duration and severity of symptoms, and the transmission rate. The paroxysmal phase is characterized by the paroxysmal cough, excessive mucus production, posttussive vomiting, and lymphocytosis that may last up to 6 weeks. This is the stage at which most children, adolescents, and adults are likely to seek medical attention and receive antimicrobial therapy. The damage that the B. pertussis cytotoxin causes—ciliostasis and death of the tracheal epithelial cells—is not reversed by the administration of an antibiotic. Thus, the cough persists. The last phase is the convalescent phase, characterized by a chronic cough that may last weeks to months. As with the paroxysmal phase, therapy given at this stage is not effective, with the exception of therapy for secondary bacterial pneumonia that develops as a complication.

Macrolide antibiotics (e.g., azithromycin, clarithromycin, and erythromycin) are the drugs of choice for treating pertussis. In addition to delay in administering antibiotics (as was the case with this child), reasons for a lack of response to therapy might include patient noncompliance. Erythromycin, in particular, is often associated with gastrointestinal intolerance. Secondary bacterial pneumonia, an occasional complication of pertussis, must also be considered in patients with persistent cough, particularly if the patient worsens clinically. Finally, the possibility that the organism is resistant to macrolides must be considered. Although macrolide-resistant B. pertussis isolates have been described, susceptibility surveys suggest resistance is still rare.

4. B. pertussis has many virulence factors that are responsible for mediating attachment to host cells and causing tissue damage. Pertussis toxin acts as both a secreted toxin and an adhesin working synergistically with filamentous hemagglutinin. Pertussis toxin belongs to the classic A-B family of ADP-ribosylating toxins (like cholera toxin and Shiga toxin). Additional toxins include adenylate cyclase-hemolysin, a cytotoxin that inhibits chemotaxis and induces apoptosis of macrophages; tracheal cytotoxin, which eliminates mucociliary clearance by ciliostasis and extrusion of ciliated cells and inhibits DNA synthesis; dermonecrotic toxin, which causes dermal necrosis and vasoconstriction; and lipopolysaccharide endotoxin, which has proinflammatory activity. Taken together, these pathogenic properties result in a grossly damaged respiratory epithelium with decreased mucociliary clearance, which puts patients at increased risk for secondary pneumonia. Also, this patient required intubation for respiratory support, which further increases the risk of health care-associated pneumonia due to organisms such as methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.

5. Historically, vaccination against pertussis was recommended at ages 2 months, 4 months, 6 months, 15 to 18 months, and 4 to 6 years. This patient was too young to have received any pertussis vaccine. Based on laboratory testing, the mother was confirmed to have pertussis, but the brother could not be confirmed due to the extended time since his illness. Nonetheless, it is probable that the brother also had pertussis. The possibilities are that neither the mother nor the brother was vaccinated against pertussis in childhood, or the fact that the protection offered by the vaccine wanes within 5 to 10 years of administration. In fact, both the mother and brother had been vaccinated in childhood, so the latter possibility is a likely explanation. Another possibility is these two individuals, closely genetically related, could not mount an immune response to the pertussis vaccine antigens. Studies have shown that vaccine-induced immunity wanes after the fifth dose of pertussis vaccine. In this case, the older sibling likely got pertussis from his peers and then infected the mother, who was infectious at the time of the infant’s birth. The infant’s lack of protective immunity, along with the high infectivity of pertussis, made it very likely that the infant would get pertussis.

Vaccination against pertussis using a whole-cell vaccine began in the 1940s. This vaccine was combined with diphtheria (D) and tetanus (T) toxoids to make the combination DTP vaccine that was given to infants and toddlers. With widespread immunization, the incidence of pertussis decreased from 157 cases per 100,000 people to <1 per 100,000 in the 1970s. However, the whole-cell vaccine was associated with increased mild side effects such as erythema, swelling, and tenderness at the injection site; fever; drowsiness; and anorexia; as well as severe side effects such as high fever and seizures. Whole-cell vaccines were considered too reactogenic for use in adolescents or adults. Acellular pertussis vaccines, which have fewer side effects, were introduced in the 1990s to replace whole-cell vaccines. These vaccines target the primary virulence factors of B. pertussis and contain purified proteins including detoxified pertussis toxins and adhesins. The acellular vaccine is combined with DT for the DTaP vaccine given to children in a five-dose series that is completed by age 4 to 6. Neither natural pertussis infection nor vaccine-induced protection provides long-term immunity. Several studies have since shown that the acellular pertussis vaccine is not as effective as the whole-cell vaccine, making children 7 to 10 years old particularly vulnerable as a reservoir of pertussis transmission. In 2012, there were >41,000 cases of pertussis reported in the United States and likely many more that were not diagnosed and/or reported. In addition, the number of outbreaks due to pertussis has increased. A well-described outbreak in California occurred in 2010 in which 89% of cases were among infants <6 months old, with the next highest incidences in those 7 to 9 years old and 10 to 18 years old. In 2012, Washington state had >2,500 pertussis cases in 6 months, with the highest incidence in infants <1 year and children aged 10, 13, and 14 years. In 2012, 49 states reported increases in pertussis cases relative to the previous year. Better detection methods (e.g., PCR) are partially responsible for this increase, but so is natural pertussis epidemiology. It has been estimated that 13 to 20% of adolescents and adults with prolonged cough have pertussis. Diagnosing older individuals with pertussis is problematic because they often have an atypical presentation consisting of nothing more than a chronic cough. However, these individuals are common sources of infant infections, particularly parents, primary caregivers, siblings, and health care workers. Since infants are at the greatest risk for serious illness and death due to pertussis, these sources of transmission are primary targets for new vaccination strategies.

In 2005, two tetanus, diphtheria, and acellular pertussis vaccines, Tdap and DTaP, were approved for administration: DTaP for people 11 to 64 years old and Tdap for those 10 to 18 years old. Tdap vaccine has reduced antigen doses for diphtheria and pertussis compared to DTaP. The Advisory Committee on Immunization Practices now recommends Tdap vaccination for 11- to 12-year-olds, adults who have not previously received Tdap or with unknown vaccine status, and pregnant women during each pregnancy. In addition, many health care institutions are requiring Tdap vaccination of all health care personnel. It is hoped that these new vaccination strategies will break the chain of transmission of a pathogen that only infects humans.

6. Hospitalized patients with pertussis should be on droplet precautions as pertussis is transmitted by large respiratory droplets produced when coughing, sneezing, or talking. Pertussis is highly communicable, with household attack rates of 80 to 100%. Droplet precautions should be maintained until the patient has received 5 days of appropriate antimicrobial therapy. There is no evidence of fomite transmission, which would require contact precautions as well. Close contacts of a person diagnosed with pertussis should be assessed for the infectiousness of the patient (e.g., which stage of disease), the intensity of the exposure, and the risks to the contact of getting pertussis or transmitting it to vulnerable populations (e.g., infants, pregnant women, and health care personnel). If warranted, postexposure prophylaxis with a macrolide should be administered to contacts within 21 days of onset of cough in the index patient. Alternatively, low-risk contacts can be monitored for pertussis symptoms for 21 days.